SU1563594A3 - Method of producing alkylenediamine derivatives - Google Patents

Abstract

Novel alkylenediamine derivative having the formula (I): <CHEM> wherein A is a group having the formula (II): R<1>(CH2)m-CH(R<2>)-(CH2)n- (II) (wherein R<1> is an aliphatic hydrocarbon group, an alicyclic group, an aryl group, or an aralkyl group; R<2> is an aliphatic hydrocarbon group, en alkoxy group, an aliphatic hydrocarbon group containing an ester or ether bonding, or an aryloxy group; and each of m and n is an integer of 0 to 2, provided that m + n does not exceed 3) and B is hoydrogen, or A is a group having the formula (III): R<3>-(CH2)k- (III) (wherein R<3> has the same meaning as that of R<1> and k is an integer of 0 to 3) and B is a group repesenting by the formula (IV): R<4>- (IV) wherein R<4> has almost the same meaning as that of R<2>, p is an integer of 2 to 6, and q is an integer of 4 to 7. These compounds are useful as glutamate blockers.

Description

The invention relates to the preparation of new heterocyclic compounds, in particular, alkylenediamine derivatives having a glutamate blocking effect, which can be used in medicine and agriculture.

The aim of the invention is to create, on the basis of known methods, a method of producing new compounds with high pharmacological activity.

Example 1. (1-pentylhex- strength) propyl piperidine.

A. A solution of 3.47 g of hydroxylamine hydrochloride in 6 ml of water and a solution of 4.77 g of potassium hydroxide in 6 ml of water are successively added to a solution of 5.11 g of 5-undecanone in 20 ml of ethanol. The resulting mixture is heated at boiling for 3 hours. Then the reaction mixture is poured into 150 ml of water containing ice. The resulting aqueous mixture is then acidified by the addition of 2N. hydrochloric acid and extracted with benzene. The organic layer is washed with a saturated aqueous solution of sodium chloride and evaporated under reduced pressure to remove the solvent. 5.57 g (the amount corresponding to the theoretical) of oxime 6-undecone was obtained in the form of a pale yellow solid.

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B. To a solution of 1.85 g of the product obtained in 140 ml of ethanol was added 140 ml of 2 and, aqueous sodium hydroxide and then 10.7 g of Rene nickel were immediately added. The resulting mixture was stirred for 1 hour, filtered and washed sequentially. water and ethanol. The filtrate and the washings were combined, diluted with water and then extracted with chloroform .. The organic layer was washed with a saturated aqueous solution of sodium chloride and evaporated under reduced pressure to remove the solvent. A pale yellow oil is obtained. This oil is purified on silica gel using column chromatography (eluent: chloroform: methanol); 100 g of b-undecanamine are obtained in the form of a colorless oil, yield 8.5%.

B. A mixture of 0.85 g of the product obtained and 0.8 g of 1- (3-chloro-propyl) piperidine is heated under nitrogen at 110-120 ° C for 3 hours. The reaction mixture is cooled and dissolved in ethanol. To the resulting solution, 0.41 ml of cond, hydrochloric acid was added. The mixture is stirred, ethyl acetate is added and the residue is left. The precipitated crystals are separated by filtration, washed with ethyl acetate and dried to obtain 640 mg of a crude crystalline product.

PRI mme R 2. 1- Cs-1.4-Methyl-1 (3-methylbutyl) pentylamino propyl {piperidine,

А, To a solution of 5.11 g 2., 8 dimetal nonan-5-one (t „bale„ 03-Ю5 ° С) 39 mm Hg. Art., get the oxidation of 2,8-dimethylnonan-5-ol by bleaching lime; 2.8-dimethyl-non-5-ol is obtained by reacting ethyl formate and isoamyl magnesium boro-amide in 20 ml of ethanol. An aqueous solution of 3.47 g of hydroxyl amine hydrochloride in 6 ml of water and a solution of 4.77 g of potassium hydroxide in 6 ml of water are successively added. The mixture is heated at boiling. The reaction mixture is then poured into 50 ml of water containing ice. The aqueous mixture is acidified by the addition of 2N. hydrochloric acid and extracted with benzene. The organic layer is washed with a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and evaporated under reduced pressure to remove the solvent. 5.21 oxime 2,8-dimethyl-nonan-5-one is obtained in the form of a pale brown oil, yield 93.7%.

B. To a solution of 2.78 g of the product obtained in 60 ml of ethanol was added 60 ml of 2N. aqueous sodium hydroxide and then immediately added 4.32 g of Rene alloy. The resulting mixture is stirred for 3 hours, filtered and washed successively with ethanol and water. The filtrate and the washings were combined, diluted with water and then extracted with chloroform. The extract is dried with anhydrous sodium sulfate and evaporated under reduced pressure to remove the solvent. A crude product is obtained containing 2,8-dimethyl-non-5-amine. It is then isolated in the form of oxalate. The oxalate was treated with aqueous sodium hydroxide to give a free base.

B. A mixture of 1.55 g of the product obtained and 1- (3-chloropropyl) piperidine is heated at 120 ° C for 3.5 hours under a nitrogen atmosphere. The reaction mixture is cooled and dissolved in 10 ml of ethanol. To this solution, 0975 ml of concentrated hydrochloric acid and ethyl acetate are added to a total volume of the mixture of 100 ml. The precipitated crystals are collected by filtration. The crystals are treated with aqueous sodium hydroxide, extracted with chloroform to obtain an oil. The oil is purified by column chromatography on silica gel (eluent chloroform - methanol) to obtain the desired product in the form of an oil. To the ethanol solution containing the resulting free base, add an insignificant excess amount of 6N. hydrochloric acid in ethanol. The mixture is evaporated to dryness. The residue is recrystallized from ethanol-ethyl acetate to form the dihydrochloride of the desired compound as a white crystalline product. Mp 249-250 ° C (decomp.).

Examples 3-21. In accordance with the synthesis procedure of Examples 1 and 2, the following compounds were prepared:

(1-benzyl-4 methylpentylamino) propyl) piperidine, m.p., 228-231 C (decomp., As dihydrochloride);

1-Ј3 (4-methyl-1-phenylpentylamino) propyl piperidine, m.p. 211-215 ° C (decomp, in the form of dihydrochloride);

1- 3- (3-iep opropyloxy-1-phenylpropylamino) propyl piperidine, m.p. 199 - 201 ° C (raslg, in the form of dihydrochloride);

(3-methylbutyloxy) 2-phenyl-ethylamino-propyl piperidine, m.p.

198-199 ° C (in the form of dihydrochloride); I, |

3-phenyl-2 (3-piperidinepropylamino) propyl-3-methylbutyrate, m.p. 189-190 ° C (decomp., In the form of dihydrochloride);

 4-methyl- - (2-phenylethyl) pentylamino propyl piperidine, m.p. 220 - 2.23 ° C (decomp., In the form of dihydrochloride);

1-p- (3-benzyl-6-methylheptylamino) propyl piperidine, m.p. 229-223 ° C (decomp., In the form of dihydrochloride);

1- 3- 4-methyl-1- (3-phenylpropyl) pentylamino Jnponttnjpiperidine, m.p. 181-181.5 C (decomp., In the form of dihydrochloride);

1-Ј3-C2,3-dimethyl-1- (3-methylbutyl) pentyl amino propyl piperidine, m.p. 179-181 ° C (decomp., In the form of difumarata);

1- {3- 1 - (- ethylpropyl) -4-methylpentylamino propyl piperidine, m.p. 210-212 C (decomp., In the form of dihydrochloride);

1- {3- 4,4-dimethyl-1- (3,3-dimethyl-butyl) pentylamino saw piperidine, t, pl. 282-284 ° C (decomp., In the form of dihydrochloride);

 1- (3-methylbutyl) hexylamino-propyl piperidine, m.p. 233-236 C (decomp., In the form of dihydrochloride);

, 4-dimethyl-1 - (3-methylbutyl) pertil methyl amino propyl piperidine, so pl. 256-263 ° C (decomp., In the form of dihydrochloride);

1- 3- 4-methyl-1- (3-methylbutyl) pentylamino-propyl pyrrolidine, m.p. 248-250 ° C (decomp., In the form of dihydrochloride);

1- {3- 4-methyl-1- (3-methylbutyl) pentyl amino propyl perhydroazepine, m.p. 220-226 ° C (decomp., In the form of dihydrochloride);

1- {3- 4-methyl-1- (3-methylbutyl) pentyl amino-propyl perhydroazecin;

1- {3- 4-methyl-1- (3-methylbutyl) pentylamino ethyl} piperidine, m.p. 261-263 ° C (decomp., In the form of dihydrochloride);

1- 4- 4-methyl-2- (3-methylbutyl) pentylamino-butylpiperidine, m.p. 263-266 ° C (decomp., In the form of dihydrochloride);

1- {5-4-methyl-1- (3-methylbutyl) pentylamino pentyl piperidine, m.p. 225-227 ° C (decomp., In the form of dihydrochloride).

Pharmacological testing. To check, use the open muscle of the first leg of the cancer. A neuromuscular sample was fixed in a vessel in which a physiological saline solution for crustaceans was circulated at a constant rate (composition: NaCl (195 mmol), CaCl (18 mmol),

Q KC1 (5.4 mmol), tris-maleic acid buffer (pH 7.5, 10 mmol) and glucose (11 mmol). A glass microelectrode filled with 3K KS1 solution is immersed in the central part

5 myofibrils and changes in the electric potential in the sarcolemma were recorded intracellularly. The glutamate blocking effect of the test compound was assessed by the definition of

0 ratios of depolarization involving 1-glutamate caused by pre-treatment with the test liquid (at concentration) for 5 minutes, which was estimated using

5 calculate 1-glutamate (concentration).

The results are presented in the table, where diltiazem is 3- (acetyloxy), 2- (dimethylamino) ethyl -2, 3-dihydro-20 (4-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one, and caroverin - (diethylamino) (4-methoxyphenyl) methyl} -2 (SHO) -quinoxalinin.

The following shows that the derivatives

, alkylenediamine have low acute and subacute toxicity.

Thus, alkylenediamine derivatives that exhibit a significant glutamate blocking effect are important as pharmaceuticals for the brain caused by an unbalanced nervous system or abnormal depression of a muscle impulse.

In addition, the alkylenediamine derivative can be used as agricultural chemicals, in particular as insecticides, because it is effective in blocking transmission to the nervous system compounds, secomas.

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Claims (2)

1. A method for preparing alkylenediamine derivatives of general formula I A-N-CCH p-NjflH H A - group of general formula II (CH2V "fHtfm Rlш R - straight or branched an aliphatic hydrocarbon group C5 -Cfe, phenyl or arkyl having 1-4 carbon atoms in the alkyl part; a straight or branched aliphatic hydrocarbon group of a C5 alkoxy group, a C3 alkoxyethyl or methQQ oxycarbonyl propyl; each is independently 0.1 or 2, provided that the sum m + n does not exceed 3 | from 2 to 5.25 from 4 to 7, differing from the fact that in general formula III R un p q where p and q have the indicated meanings. 2. A method according to claim 1, characterized in that the reaction of compounds III and IV is carried out at 110-120 ° C. A-NHlt where A has the indicated value, is reacted with a compound of general formula IV Cl-CC VN CHlH zo Diltiazem and caroverin are used at a dose, while compounds prepared in accordance with the inventive method are used at a dose of 2- M.